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As part of our ongoing program to develop probes for the hormone binding domain of the estrogen receptor-α (ERα), we prepared and evaluated a series of 17α,Z-(4-substituted-phenyl)vinyl estradiol derivatives. The results indicated that the relative binding affinities (RBAs) at 25 °C for the new compounds were significant (RBA = 9−57) although less than that of estradiol (RBA = 100) or of the parent unsubstituted phenylvinyl estradiol (RBA = 66). All of the Z-compounds were full agonists in the uterotrophic assay, indicating that the ligands formed estrogen-like complexes with the estrogen receptor-α hormone binding domain (ERα-HBD). Comparison of corresponding Z- and E-4-substituted phenylvinyl ligands complexed with the ERα-HBD indicated small but significant differences in binding modes that may account for the differing trends seen in the structure−activity relationships for the two series.

As part of our program to develop probes for the hormone binding domain of the estrogen receptor α (ERα), we prepared a series of 4-para-substituted phenylvinyl estradiol derivatives using a combination of solution and solid-phase Pd(0)-catalyzed methods. The compounds 5a−j were evaluated for their binding affinity using the ERα hormone binding domain (HDB) isolated from transfected BL21 cells. The results indicated that although the new compounds were somewhat lower in relative binding affinity (RBA at 25 °C is 1−60%) than estradiol (100%), most had higher affinity than the unsubstituted parent phenylvinyl estradiol (RBA = 9%). Because the substituents did not generate a structure−activity relationship directly based on physicochemical properties, the series was evaluated using molecular modeling and molecular dynamics to determine key interactions between the ligand, especially the para substituent, and the protein. The results suggest that the observed relative binding affinities are directly related to the calculated binding energies and that amino acids juxtaposed to the para position play a significant but not dominant role in binding. In conclusion, we have identified the 17α-E-(4-substituted phenyl)vinyl estradiols as a class of ligands that retain significant affinity for the ERα-HBD. In particular, 4-substitution tends to increase receptor affinity compared to the unsubstituted analogue, as exemplified by 5e (4-COCH3), which had the highest RBA value (60%) of the series. Palladium(0)-catalyzed coupling reactions on solid support or in solution using suitably substituted iodo arenes and 17α-E-tributylstannylvinyl estradiols offer a flexible approach to their preparation. Molecular modeling studies of the receptor suggest that there exists additional ligand accessible regions within the ERα-HBD to generate interactions that may enhance receptor affinity or modify efficacy in developing new therapeutic agents. Studies to undertake modification in the properties and/or position of the aryl substituents in subsequent series to further define that role are in progress.

To test the hypothesis that bradykinin effects cutaneous active vasodilation during hyperthermia, we examined whether the increase in skin blood flow (SkBF) during heat stress was affected by blockade of bradykinin B2receptors with the receptor antagonist HOE-140. Two adjacent sites on the forearm were instrumented with intradermal microdialysis probes for local delivery of drugs in eight healthy subjects. HOE-140 was dissolved in Ringer solution (40 μM) and perfused at one site, whereas the second site was perfused with Ringer alone. SkBF was monitored by laser-Doppler flowmetry (LDF) at both sites. Mean arterial pressure (MAP) was monitored from a finger, and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). Water-perfused suits were used to control body temperature and evoke hyperthermia. After hyperthermia, both microdialysis sites were perfused with 28 mM nitroprusside to effect maximal vasodilation. During hyperthermia, CVC increased at HOE-140 (69 ± 2% maximal CVC, P< 0.01) and untreated sites (65 ± 2% maximal CVC, P< 0.01). These responses did not differ between sites (P> 0.05). Because the bradykinin B2-receptor antagonist HOE-140 did not alter SkBF responses to heat stress, we conclude that bradykinin does not mediate cutaneous active vasodilation.

Following the phenomenal success of second generation global system for mobile communications (GSM) systems, the world has turned its attention to third generation mobile systems (3G). New radio spectrum has been allocated for these networks and over the last 12 months there has been global activity to license this spectrum. Licences have been awarded in a number of ways including 'beauty contests' and (often costly) auctions. Technologists have joined forces to specify the standards for 3G. This paper describes the drivers for 3G and the commercial model that is emerging. The benefits that 3G technology will provide for business and consumer products are identified. A component-based approach to application and product development is described, based on the important value add features of mobile systems. Finally, mobile terminals, billing and payment, and customer care are also considered as they are vital to the overall customer experience.